1. Field of the Invention
The present invention relates to a pharmaceutical dosage form of fenofibrate having enhanced bioavailability, as well as to an advantageous process for making the same.
2. Description of the Background
Fenofibrate or P-(4-chlorobenzoyl)-phenoxy isobutyrate isopropyl ester is useful for the treatment of adult patients with very high elevations of serum triglyceride levels and/or cholesterol levels. The usual daily dosage is 300 mg which is administered in two or three doses. Fenofibrate is absorbed as fenofibric acid which is responsible for the pharmacological activity. Fenofibric acid resulting from the hydrolysis of fenofibrate is extensively bound to plasma albumin. The plasma half-life is about 20 hours. Fenofibric acid is excreted predominantly in the urine, mainly as the glucuronide conjugate, but also as a reduced form of fenofibric acid and its glucuronides.
Fenofibrate, is presently available in a pharmaceutical dosage form consisting of hard gelatin capsules containing fenofibrate, lactose starch and magnesium stearate. After oral administration, during a meal, about 60% of the dose of this conventional form is effectively absorbed and found in the blood as fenofibric acid, the main metabolite responsible for pharmacological activity. (Strolin & A1, Act Pharmacal. Toxicol. 1986; 59 (Suppl. 5); 167).
The first attempt to improve the bioavailability of fenofibrate was performed by Ben-Armor and A1, by solubilizing the fenofibrate in dimethyl isosorbide, a nonaqueous solvent with a miscible wetting agent (Labrafil M1944CS) with HLB of between 3-4. In order to use the product in capsules, colloidal silicon oxide was added to increase the viscosity. The liquid so obtained was placed in hard gelatin capsules which, to be leak proof, were sealed. In vivo studies with this formulation indicate that there was no statistically significant difference in bioavailability between this liquid formulation and the conventional form when the product was given with food.
European Patent Application 0330532 discloses a fenofibrate composition wherein the fenofibrate powder is co-micronized with a solid wetting agent. Sodium lauryl sulfate is described as the solid wetting agent of choice. The co-micronized powder so obtained is mixed with capsule filling excipient such as lactose, starch, polyvinyl pyrollidone and magnesium stearate. A formulation of this composition is actually available on the French market under the trade name Lypantyl 200 M.RTM.. A study comparing this formulation (Lypantyl 200 M.RTM.) to the conventional form was undertaken and a statistically significant increase in bioavailability was indicated for the former. In particular, it was found that 67 mg of the new form gives the same amount absorbed as does 100 mg of the conventional form. (J. L. Suichard & Al Cun Therapeutic Research Vol. 54, NS, Nov. 1993).
Unfortunately, co-micronization of the active drug fenofibrate with the wetting agent sodium lauryl sulfate, although necessary, is a time consuming and costly operation. Further, an inherent drawback of micronization is that the material obtained must comply with very stringent particle size specifications.
Moreover, the filling of hard gelatin capsules with a micronized powder is a difficult operation, particularly if weight variation homogeneity is considered.
Hence, a need exists for a fenofibrate formulation that avoids the use of co-micronization, while providing a bioavailability comparable to that afforded by the conventional fenofibrate formulation which uses co-micronization.